Infants born small for dates have an increased risk of health problems later in life. These include hypertension, cardiovascular disease, and noninsulin dependent diabetes mellitus (NIDDM). These risks are not limited to the first generation; rather, subsequent generations can also be demonstrated to have an increased incidence of NIDDM. The process by which abnormalities in the intrauterine environment result in adult disease has been tabbed as programming. Substrate flow from mother to fetus occurs via the placenta. Of particular potential import to fetal glucose homeostasis, particularly in times of stress, are placental glucose transporters, GLUT1 and GLUT3, and placental amino acid transport System A, responsible for the Na+-dependent transfer of small neutral amino acids including alanine, an important gluconeogenic precursor. The proposed research will utilize a well characterized maternal low-protein diet model to address the hypotheses that 1) maternal-fetal nutrient transfer as mediated by GLUT 1/3 (glucose transfer) and ATA2 (System A amino acid transport) is diminished in IUGR placentas derived from these pregnancies and 2) that, despite a relatively normal intrauterine environment, placental glucose and amino acid transfer and homeostasis are persistently abnormal in the progeny of these IUGR animals. In order to accomplish these goals, the in vivo transfer of nonmetabolizable substrates of these transport systems will be examined in both generations. Transporter expression within the placenta will be examined at the protein level by utilizing apical and basal membrane vesicles for immunoblot analysis using well validated antibodies against GLUT1 and GLUT3, and an antibody from our laboratory against ATA2. mRNA expression will be examined by Northern analysis using full length cDNAs representing each transport protein. The fetal metabolic milieu will be explored by examination of protein synthesis/accretion rates, and determination of the contribution of endogenous glucose production within the fetus. Through these studies, the involvement of placental nutrient transfer in "programming" fetal development will be determined, providing a springboard both to better understanding of this phenomena, as well as a target for development for future therapeutic interventional strategies.